Among healthy populations, the benefits of moderate alcohol consumption are well documented. However, more than 7.5 million Americans are survivors of myocardial infarction (MI) and the epidemic of obesity has given rise to an even larger unhealthy population with dyslipidemia,hypertension, low HDL-C, and hyperglycemia (i.e. metabolic syndrome). The influence that alcohol has on prognosis among these "at risk" groups is crucial for informed decision-making by patients, physicians, and policy-makers. We propose to examine alcohol and chronic disease in vulnerable populations among 121,700 women (32,826 with stored blood samples) in the Nurses' Health Study (1976-2006) and 51,529 men (18,100 with stored blood samples) in the Health Professionals Follow-up Study (1986-2006). First, we will study alcohol intake and risk of mortality among an estimated 3,345 women and 2,835 men with confirmed incident non-fatal MI. Secondly, using blood markers of dyslipidemia and abnormal glucose homeostasis, we will examine alcohol and coronary heart disease (CHD) among participants with metabolic syndrome in a nested case control (1:2) study among the projected 680 women and 534 men who provided blood samples and subsequently developed CHD. Finally, because the purported benefit of alcohol consumption is attributed principally to increased HDL-C, we will examine CHD risk associated with gene-alcohol interactions in genes that modulate HDL-C levels. Specifically, alcohol dehydrogenase-3, hepatic lipase, lipoprotein lipase, cholesteryl ester transport protein, and endothelial lipase. The well characterized large cohorts of women and men with stored blood samples provide an unparalleled opportunity to elucidate the health effects of alcohol among high risk patients. Furthermore, knowledge of populations that may benefit from alcohol (or be at greatest risk) will help in the understanding of the pathophysiology of CHD and aid in the development of more complete clinical guidelines for the growing population of individuals at risk for coronary disease and mortality.